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https://hdl.handle.net/2440/105130
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Type: | Journal article |
Title: | The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins |
Author: | Obayed Ullah, M. Ve, T. Mangan, M. Alaidarous, M. Sweet, M. Mansell, A. Kobe, B. |
Citation: | Acta Crystallographica Section D: Biological Crystallography, 2013; 69(12):2420-2430 |
Publisher: | Wiley |
Issue Date: | 2013 |
ISSN: | 0907-4449 1399-0047 |
Statement of Responsibility: | M. Obayed Ullah, Thomas Ve, Matthew Mangan, Mohammed Alaidarous, Matthew J. Sweet, Ashley Manselld and Bostjan Kobe |
Abstract: | TRIF/TICAM-1 (TIR domain-containing adaptor inducing interferon-[beta]/TIR domain-containing adaptor molecule 1) is the adaptor protein in the Toll-like receptor (TLR) 3 and 4 signalling pathway that leads to the production of type 1 interferons and cytokines. The signalling involves TIR (Toll/interleukin-1 receptor) domain-dependent TRIF oligomerization. A protease-resistant N-terminal region is believed to be involved in self-regulation of TRIF by interacting with its TIR domain. Here, the structural and functional characterization of the N-terminal domain of TRIF (TRIF-NTD) comprising residues 1-153 is reported. The 2.22 Å resolution crystal structure was solved by single-wavelength anomalous diffraction (SAD) using selenomethionine-labelled crystals of TRIF-NTD containing two additional introduced Met residues (TRIF-NTDA66M/L113M). The structure consists of eight antiparallel helices that can be divided into two subdomains, and the overall fold shares similarity to the interferon-induced protein with tetratricopeptide repeats (IFIT) family of proteins, which are involved in both the recognition of viral RNA and modulation of innate immune signalling. Analysis of TRIF-NTD surface features and the mapping of sequence conservation onto the structure suggest several possible binding sites involved in either TRIF auto-regulation or interaction with other signalling molecules or ligands. TRIF-NTD suppresses TRIF-mediated activation of the interferon-[beta] promoter, as well as NF-[kappa]B-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation. |
Keywords: | Adaptor Proteins, Vesicular Transport |
Rights: | © 2013 International Union of Crystallography Printed in Singapore – all rights reserved |
DOI: | 10.1107/S0907444913022385 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1003326 http://purl.org/au-research/grants/arc/FT100100657 http://purl.org/au-research/grants/nhmrc/1003470 |
Published version: | http://dx.doi.org/10.1107/s0907444913022385 |
Appears in Collections: | Agriculture, Food and Wine publications Aurora harvest 3 |
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